Originator
Longum,Farmitalia,W. Germany,1962
Manufacturing Process
2-Amino-3,5-Dibromo-Pyrazine: 112.7 ml of bromine in 375 ml of acetic acid
are slowly added at 0° to +2°C, while stirring, to a solution of 95.11 grams of
2-amino-pyrazine and 326.5 grams of acetic acid trihydrate (CH3COONa·3H2O)
in 1,480 ml of acetic acid. This addition requires about 2 to 3 hours and it is
carried out in the dark. The mixture is then allowed to stand at room
temperature (25° to 30°C) for 15 to 16 hours. About 1.5 liters of acetic acid
are distilled off under vacuum (12 to 14 mm Hg) at 35°C and the brown and
viscous residue is poured into 500 grams of ice-water under stirring.
Aqueous 20% sodium hydroxide is added in order to obtain a pH = 8 and then
the product is filtered and air-dried. The air-dried product is extracted 6 times
with 150 ml of ether; the filtered ethereal solutions are evaporated to dryness
and the residue (50 to 52 grams) is crystallized from hot water. The yield is
34.36 grams, melting at 114°C.
2-Amino-3-Methoxy-5-Bromo-Pyrazine: 7 grams of 2-amino-3,5-dibromopyrazine
are boiled for 9 hours in a methanolic solution of sodium methylate
(obtained from 0.65 gram of Na and 18.5 ml of methanol). By cooling a
crystalline product is obtained, filtered and washed once with methanol and 2
to 3 times with water. The yield is 5.4 grams, melting at 138°C.
2-Amino-3-Methoxy-Pyrazine: 3 grams of 2-amino-3-methoxy-5-bromopyrazine
are hydrogenated, in methanolic solution at room temperature and at
atmospheric pressure, in the presence of 1 gram of palladium over charcoal (10%) and 0.9 gram of potassium hydroxide. When the stoichiometric amount
of hydrogen is absorbed, the suspension is filtered and the filtrate is
evaporated to dryness. The residue is extracted with acetone, the acetonic
solution is evaporated and the residue (1.8 grams, melting at 75° to 82°C) is
crystallized from cyclohexane. The yield is 1.5 grams, melting at 85°C.
2-(p-Acetylaminobenzene-sulfonamido)-3-Methoxy-Pyrazine: 1.5 grams of 2-
amino-3-methoxy-pyrazine dissolved in 15 ml of anhydrous pyridine are
treated, under cooling and stirring, with 2.81 grams of pacetylaminobenzenesulfonyl
chloride, at small portions in about 30 minutes.
The mixture is allowed to stand for 20 hours at room temperature and then is
heated to 50°C for 4 hours.
The solution is concentrated to one-third of its volume, under vacuum, and
poured into ice-water under stirring. The precipitate is filtered and washed
with water. 2.21 grams melting at 218° to 220°C are obtained. The MP
(crystallized from alcohol) is 224°C.
2-Sulfanilamido-3-Methoxy-Pyrazine: 1.5 grams of the product from the
preceding step and 7 to 8 ml of aqueous 10% sodium hydroxide are boiled for
1 hour. The cooled solution is slightly acidified to pH 6 with aqueous 2 N
hydrochloric acid and the product is filtered. The yield is 1.25 grams, melting
at 175°C.
Pharmaceutical Applications
2-Sulfanilamido-3-methoxypyrazine. A very long-acting
compound (plasma half-life 60 h). Adequate blood levels
can be maintained by giving a dose of 2 g once weekly.
The protein binding is c. 70%. It has been successfully used
in the single-dose treatment of urinary tract infection. As
with other long-acting compounds, sulfametopyrazine has
been associated with an increased incidence of erythema
multiforme.
Synthesis
Sulfalene, 3-methoxy-2-sulfanilamidopyrazine (33.1.41), like other sulfanilamides, is synthesized by the standard scheme from 4-acetylaminobenzenesulfonyl chloride,
which is reacted with 3-amino-2-methoxypyrazine, which is synthesized by two technologically available methods. The first of these methods consists of direct bromination of 2-aminopyrazine using acetic acid as a solvent, which gives 3,5-dibromo-2-aminopyrazine (33.1.34).
Reacting this with sodium methoxide gives 3-methoxy-5-bromo-2-aminopyrazine (33.1.35).
Hydrogen reduction using a palladium on carbon catalyst replaces the bromine atom at C5 of
the product with a hydrogen atom, giving 3-methoxy-2-aminopyrazine (33.1.36).
This same 3-methoxy-2-aminopyrazine (33.1.36) is synthesized from 3-hydroxypyrazin-
2-carboxamide. Reacting this with phosphorous oxychloride replaces the hydroxyl group
with a chlorine atom while the carboxamide group simultaneously undergoes dehydration
to form 3-chloro-2-cyanopyrazine (33.1.37). Next, reacting this with sodium methoxide
gives 3-methoxy-2-cyanopyrazine (33.1.38). The cyano group in this compound is
hydrolyzed by a base in the presence of hydrogen peroxide to a carboxamide group, giving
3-methoxy-2-carboxamideopyrazine (33.1.39). The resulting product undergoes a Hofmann
rearrangement when reacted with sodium hypochlorite, giving the desired 3-methoxy-2
aminopyrazine (33.1.36). Reacting this with 4-acetylaminobenzenesulfonyl chloride and
subsequent hydrolysis of the acetyl group with a base to (33.1.40) gives sulfalene.
